Kuru is an invariably fatal, neurodegenerative and infectious disease that falls under the same group of neurodegenerative disorders as Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker Disease, fatal familial insomnia, and variable protease-sensitive prionopathy (PSPr). These transmissible spongiform encephalopathies (TSEs) are caused by a malformation of the prion protein, specifically the aggregate of a misfolded isoform (PrPSc) of a normally functioning cellular glycoprotein (PrPc) [1]. Prions are abnormal, pathogenic agents that induce abnormal folding of normal cellular proteins that are mostly found in the brain, leading to brain damage [2].
Kuru is a disease restricted to the natives of the Fore people in Papua New Guinea transmitted through ritualistic endocannibalism practices. Kuru seems to appear around the beginning of the twentieth century, with the onset of the first cases in the 1920s. The disease mostly affected women and children, as they were given the brains of the corpses of their dead relatives as a mark of respect [3]. Incubation period of Kuru range from 5 to 27 years and the duration of the disease from the start of symptoms until death is about one year [4]. Symptoms of kuru include ataxia, tremors, and emotional changes such as uncontrollable laughter. Contrary to its more prevalent counterpart, Creutzfeldt-Jakob disease, victims of kuru do not display signs of dementia.
There are three stages of kuru symptoms: ambulant (headaches and limb pains), sedentary (ataxia and tremor), and terminal (bedridden with dysphasia) [1]. Recent research has shown that most elderly survivors of the kuru epidemic in the mid 1950s are heterozygotes for codon 129 of the prion protein gene PRNP [5]. Figure 1 below shows a comparison of brain sections between victims with normal brain, kuru-infected brain, Creutzfeldt-Jakob disease, and scrapie. Kuru prions mostly affect the cerebellum, inducing muscle weakness, loss of coordination, tremors, and spontaneous episodes of laughter or crying [8].
Figure 1: Comparison of brain sections between a normal, kuru-infected, CJD, and scrapie animal [7].
TARGET INFORMATION:
Doxycycline has been used to target the protease-resistant PrPSc in Creutzfeldt-Jakob disease, a neurodegenerative prion disease similar to kuru. The PrPSc is a mutated, disease-causing isoform of PRNP gene (prion protein) in humans. Research on doxycycline and tetracycline controlled transactivator (tTA) in transgenic mice is proving to control the conversion of non-disease-causing prion protein PrPc to the pathogenic isoform of PrPSc during a posttranslational modification [6]. Possible roles of PrPc include cell-cell adhesion and intracellular signaling, although there are no known functions of PrPc in the brain, and animals still developed normally even if they are PrP-deficient [6]. However, two studies reported that PrP-deficient mice had defective sleep-wake cycles and altered circadian rhythms. As discussed above, these prion glycoproteins are mostly found in the brain and cell membranes as well as mitochondria. PrPSc is a conformational isoform that accumulates in a compacted, protease-resistant form within the neural tissue. The abnormal PrPSc has identical primary structures as its normal counterpart PrPc but different secondary and tertiary structures [1].
Figure 2: Difference in structure between PrPc and PrPSc prion proteins. The mutated PrPSc protein possess a higher proportion of β-sheet structure in place of the normal α-helix structure, forming highly structured amyloid fibers that may accumulate as plaque.
DRUG INFORMATION:
The treatment of doxycycline for Creutzfeldt-Jakob disease is not generally used to treat Kuru since simple prevention such as avoiding cannibalistic practices can significantly reduce transmission of the disorder.
In one study, doxycycline proved to be effective in reverting the protease-resistance of PrPSc from analysis of Creutzfeldt-Jakob disease, reducing infectivity of the disease, and prolonging survival of the infected animal [6]. Doxycycline serves to inhibit the posttranslational modification of PrPc into the disease-causing isoform PrPSc. In the same double-blind, placebo-controlled, parallel groups clinical trial, doxycycline was administered at a single oral dose of 100mg per day. In another animal study, minimal benefit was shown when doxycycline was administered using intraventricular liposomal delivery, not oral delivery as tested in the clinical trial [6]. The clinical trial treated 31 Creutzfeldt-Jakob disease patients with doxycycline and 35 with the placebo. The results of the trial proved that doxycycline is most effective towards females as it prolonged trial patients’ lives from clinical onset of disease to their deaths. However, in the efficacy analyses, there is no significant difference between patients treated with doxycycline and those treated with the placebo in regard to the rate of the disease’s progression. Thus
Doxycycline hyclate is an antibiotic synthetically derived from oxytetracycline with a molecular formula of C22H24N2O8H2O and a molecular weight 462.46 g/mol [5]. Figure 3 and 4 below shows the schematic figure of the drug in 2D and 3D view, respectively.
Figure 3: Schematic figure of Doxycycline hyclate in 2D view [5].
Figure 4: Schematic figure of Doxycycline hyclate in 3D view [5].
Doxycycline are readily absorbed and bound to plasma proteins concentrated by the liver in the bile and excreted in fecal matter at high concentrations and biologically active form [5].
Side effects from this drug includes:
slight diarrhea
nausea
skin rashes
intracranial hypertension in adults
other gastrointestinal lesions [5].
According to the U.S. Patent and Trademark Office, doxycycline hyclate has been patented. Being a tetracycline antibiotic, doxycycline is commonly used to treat a variety of infections. The company Pfizer earned the US Food and Drug Administration approval to bring doxycycline to mass market under the name Vibramycin. Other names include Monodox, Microdox, Periostat, and Doxyhexal [5].
Doxycycline is also used to treat:
Rocky Mountain spotted fever
Rickettsialpox
Cholera
Shigella
among other respiratory tract infections [5].
Other studies on transmissible spongiform encephalopathies or prion diseases using a different drug, quinacrine, have been conducted to further develop a cure for Creutzfeldt-Jakob disease.
REFERENCES:
[1] G. Zanusso, M. Fiorini, S. Ferrari, K. Meade-White, I. Barbieri, E. Brocchi, B. Ghetti, S. Monaco, Gerstmann-Straussler-Scheinker disease and “anchorless prion protein” mice share prion conformational properties diverging from sporadic Creutzfeldt-Jakob disease. Journal of Biological Chemistry2014, 289, (5).
[2] John Collinge, Jerome Whitfield, Edward Mckintosh, John Beck, Simon Mead, Dafydd J. Thomas, Michael P. Alpers, Kuru in the 21st century – an acquired human prion disease with very long incubation periods. The Lancet2006, 367, (9528), 2068-2074.
[3] Stephanie Haik, Gabriella Marcon, Alain Mallet, Mauro Tettamanti, Arlette Welaratne, Doxycycline in Creutzfeldt-Jakob disease: a phase 2, randomized, double-blind, placebo-controlled trial. The Lancet2014, 13, (2), 150-158.
[4] Prion Diseases. Centers for Disease Control and Prevention 2012.
[6] J.N. Huillard d’Aignaux, S.N. Cousens, J. Maccario, D. Costagliola, M.P. Alpers, P.G. Smith, A. Alperovitch, The incubation period of kuru. Epidemiology2002, 13, (4), 402-408.
Kuru/Doxycycline
MOTIVATION AND BACKGROUND:
Kuru is an invariably fatal, neurodegenerative and infectious disease that falls under the same group of neurodegenerative disorders as Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker Disease, fatal familial insomnia, and variable protease-sensitive prionopathy (PSPr). These transmissible spongiform encephalopathies (TSEs) are caused by a malformation of the prion protein, specifically the aggregate of a misfolded isoform (PrPSc) of a normally functioning cellular glycoprotein (PrPc) [1]. Prions are abnormal, pathogenic agents that induce abnormal folding of normal cellular proteins that are mostly found in the brain, leading to brain damage [2].
Kuru is a disease restricted to the natives of the Fore people in Papua New Guinea transmitted through ritualistic endocannibalism practices. Kuru seems to appear around the beginning of the twentieth century, with the onset of the first cases in the 1920s. The disease mostly affected women and children, as they were given the brains of the corpses of their dead relatives as a mark of respect [3]. Incubation period of Kuru range from 5 to 27 years and the duration of the disease from the start of symptoms until death is about one year [4]. Symptoms of kuru include ataxia, tremors, and emotional changes such as uncontrollable laughter. Contrary to its more prevalent counterpart, Creutzfeldt-Jakob disease, victims of kuru do not display signs of dementia.
There are three stages of kuru symptoms: ambulant (headaches and limb pains), sedentary (ataxia and tremor), and terminal (bedridden with dysphasia) [1]. Recent research has shown that most elderly survivors of the kuru epidemic in the mid 1950s are heterozygotes for codon 129 of the prion protein gene PRNP [5]. Figure 1 below shows a comparison of brain sections between victims with normal brain, kuru-infected brain, Creutzfeldt-Jakob disease, and scrapie. Kuru prions mostly affect the cerebellum, inducing muscle weakness, loss of coordination, tremors, and spontaneous episodes of laughter or crying [8].
TARGET INFORMATION:
Doxycycline has been used to target the protease-resistant PrPSc in Creutzfeldt-Jakob disease, a neurodegenerative prion disease similar to kuru. The PrPSc is a mutated, disease-causing isoform of PRNP gene (prion protein) in humans. Research on doxycycline and tetracycline controlled transactivator (tTA) in transgenic mice is proving to control the conversion of non-disease-causing prion protein PrPc to the pathogenic isoform of PrPSc during a posttranslational modification [6]. Possible roles of PrPc include cell-cell adhesion and intracellular signaling, although there are no known functions of PrPc in the brain, and animals still developed normally even if they are PrP-deficient [6]. However, two studies reported that PrP-deficient mice had defective sleep-wake cycles and altered circadian rhythms. As discussed above, these prion glycoproteins are mostly found in the brain and cell membranes as well as mitochondria. PrPSc is a conformational isoform that accumulates in a compacted, protease-resistant form within the neural tissue. The abnormal PrPSc has identical primary structures as its normal counterpart PrPc but different secondary and tertiary structures [1].
DRUG INFORMATION:
The treatment of doxycycline for Creutzfeldt-Jakob disease is not generally used to treat Kuru since simple prevention such as avoiding cannibalistic practices can significantly reduce transmission of the disorder.
In one study, doxycycline proved to be effective in reverting the protease-resistance of PrPSc from analysis of Creutzfeldt-Jakob disease, reducing infectivity of the disease, and prolonging survival of the infected animal [6]. Doxycycline serves to inhibit the posttranslational modification of PrPc into the disease-causing isoform PrPSc. In the same double-blind, placebo-controlled, parallel groups clinical trial, doxycycline was administered at a single oral dose of 100mg per day. In another animal study, minimal benefit was shown when doxycycline was administered using intraventricular liposomal delivery, not oral delivery as tested in the clinical trial [6]. The clinical trial treated 31 Creutzfeldt-Jakob disease patients with doxycycline and 35 with the placebo. The results of the trial proved that doxycycline is most effective towards females as it prolonged trial patients’ lives from clinical onset of disease to their deaths. However, in the efficacy analyses, there is no significant difference between patients treated with doxycycline and those treated with the placebo in regard to the rate of the disease’s progression. Thus
Doxycycline hyclate is an antibiotic synthetically derived from oxytetracycline with a molecular formula of C22H24N2O8H2O and a molecular weight 462.46 g/mol [5]. Figure 3 and 4 below shows the schematic figure of the drug in 2D and 3D view, respectively.
Doxycycline are readily absorbed and bound to plasma proteins concentrated by the liver in the bile and excreted in fecal matter at high concentrations and biologically active form [5].
Side effects from this drug includes:
According to the U.S. Patent and Trademark Office, doxycycline hyclate has been patented. Being a tetracycline antibiotic, doxycycline is commonly used to treat a variety of infections. The company Pfizer earned the US Food and Drug Administration approval to bring doxycycline to mass market under the name Vibramycin. Other names include Monodox, Microdox, Periostat, and Doxyhexal [5].
Doxycycline is also used to treat:
- Rocky Mountain spotted fever
- Rickettsialpox
- Cholera
- Shigella
- among other respiratory tract infections [5].
Other studies on transmissible spongiform encephalopathies or prion diseases using a different drug, quinacrine, have been conducted to further develop a cure for Creutzfeldt-Jakob disease.REFERENCES:
[1] G. Zanusso, M. Fiorini, S. Ferrari, K. Meade-White, I. Barbieri, E. Brocchi, B. Ghetti, S. Monaco, Gerstmann-Straussler-Scheinker disease and “anchorless prion protein” mice share prion conformational properties diverging from sporadic Creutzfeldt-Jakob disease. Journal of Biological Chemistry 2014, 289, (5).
[2] John Collinge, Jerome Whitfield, Edward Mckintosh, John Beck, Simon Mead, Dafydd J. Thomas, Michael P. Alpers, Kuru in the 21st century – an acquired human prion disease with very long incubation periods. The Lancet 2006, 367, (9528), 2068-2074.
[3] Stephanie Haik, Gabriella Marcon, Alain Mallet, Mauro Tettamanti, Arlette Welaratne, Doxycycline in Creutzfeldt-Jakob disease: a phase 2, randomized, double-blind, placebo-controlled trial. The Lancet 2014, 13, (2), 150-158.
[4] Prion Diseases. Centers for Disease Control and Prevention 2012.
[5] PubChem. Compound. Doxycycline. http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=54671203 (accessed Feb 2, 2014).
[6] J.N. Huillard d’Aignaux, S.N. Cousens, J. Maccario, D. Costagliola, M.P. Alpers, P.G. Smith, A. Alperovitch, The incubation period of kuru. Epidemiology 2002, 13, (4), 402-408.
[7] University of Utah Health Sciences. Genetic Science Learning Center. Prions: On the Trail of Killer Proteins. http://learn.genetics.utah.edu/content/molecules/prions (accessed Feb 17, 2014).